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In establishing a link between the Aβ and tau pathologies, Zhang and colleagues used an elegant screening approach called random homozygous gene perturbation (RHGP). It allowed them, in mouse N2a cells, to identify a retrotransposed gene that “interacted” with APP/Aβ by causing increased surface accumulation of APP βCTF. It turned out when transfecting this gene into several different cell lines from a range of species, that this causes an interaction with adenylate cyclases, activating the kinase PKA, which then inactivates GSK3, which, having both tau and APP as substrate, results in reduced tau phosphorylation and Aβ production.

It is interesting to see that GSK3 is the common denominator and any protein in the PKA/GSK cascade seems to be a suitable drug target. The authors move on to generate an Rps23r1 transgenic mouse strain, which they cross with the triple AD mouse generated by Salvatore Oddo and Frank LaFerla. The authors show that this is beneficial with regard to GSK3 activity, tau phosphorylation, and Aβ formation. Whether humans have a homologue of Rps23r1 is not known, as the authors of the study point out. They speculate what the implications might be “should humans lack Rps23r1 homologues.” It would be interesting to know whether they have found more novel genes in the course of the RHGP screening and, if so, whether these fall into distinct categories.

This manuscript shows the value of functional genetics screens in identifying previously unrecognized modulators of GSK3 function, and emphasizes the centrality of dynamic tau phosphorylation as a key mechanism in AD pathology. When the functional role of this type of novel component is fully understood, it may offer a route toward understanding the basis of therapeutic response as one element. Previous attempts to link GSK3 to both pathologies have been inconclusive since not all GSK3 inhibitors inhibit both Aβ and tau phosphorylation and even if some of them do, there is a clear disconnect between the concentrations needed to reduce Aβ levels, and tau phosphorylation. The identification of Rps23r1 clearly represents an important step in identifying common pathways that regulate both Aβ levels and tau phosphorylation. The authors provide convincing evidence of this in the triple transgenic mouse. Equally important is the fact that this protein exerts its effects in human cells. Although Rsp23r1 itself may not be amenable as a drug discovery approach, negative regulators of this pathway either upstream or downstream may prove to be of value in Alzheimer disease.